Opioid Mediated Adenylyl Cyclase Supersensitization

阿片类药物介导的腺苷酸环化酶超敏化

• 批准号: 7125622
• 负责人: MARY F DIVIN
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125622
• 关键词: adenylate cyclase; behavior test; biological signal transduction; brain cell; cAMP response element binding protein; cell surface receptors; drug hypersensitivity; drug withdrawal; laboratory mouse; mitogen activated protein kinase; opiate alkaloid; opioid receptor; phosphorylation; protein isoforms; receptor coupling; receptor expression; tissue /cell culture; toxicant interaction

DESCRIPTION (provided by applicant): Adverse withdrawal effects often result from discontinuation of opioid use. Upon chronic treatment and subsequent removal of opioids, cells exhibit an enhanced sensitivity to cAMP accumulation, termed adenylyl cyclase supersensitization. It is hypothesized that opioid induced adenylyl cyclase supersensitization results from stimulation of specific Galpha subtypes and subsequent activation of the MAP kinase pathway. This hypothesis will be tested in cellular models, in ex vivo tissue preparations, and in whole animal behavioral models. Supersensitization may be supported by specific oj/o subtypes, and this will be investigated through the use of pertussis toxin insensitive Galpha proteins expressed in SH-SY5Y and C6n cells.The role of MAP kinase in adenylyl cyclase supersensitization will be examined by relating the time courses of supersensitization and MAP kinase induction, and using inhibitors of the MAP kinase pathway in cellular and animal models. Through the use of various jo,- and 8-opioid agonists, it will be determined if mu- and delta-opioid receptors, or interactions between them, differently modulate supersensitization. Understanding the cellular responses to opioids and how this relates to the whole animal is essential in providing both analgesic treatment and therapy for the consequences of chronic opioid abuse and withdrawal.

描述（由申请人提供）： 不良戒断效果通常是由于停止使用阿片类药物的使用而导致的。经过长期治疗和随后的阿片类药物去除后，细胞对cAMP积累的敏感性增强，称为腺苷环酶超敏化。假设阿片类药物诱导的腺苷酸环化酶超敏化是由于特定的Galpha亚型的刺激以及随后的MAP激酶途径的激活。该假设将在细胞模型，离体组织制剂和整个动物行为模型中进行检验。特定的OJ/O亚型可以支持过度敏化，这将通过使用百日咳毒素不敏感的Galpha蛋白来研究，以SH-SY5Y和C6N细胞表达的百日咳毒素不敏感的Galpha蛋白。细胞和动物模型中的激酶途径。通过使用各种JO， - - 和8-阿片类动力学家，可以确定Mu-和delta-阿片受体或它们之间的相互作用是否不同地调节超敏化。了解细胞对阿片类药物的反应以及与整个动物的关系，对于提供镇痛治疗和治疗，以造成慢性阿片类药物滥用和戒断的后果至关重要。